This proposal is directed to the elucidation of mechanisms for transport of pharmacologically active weak electrolytes across the epithelia lining the gastro-intestinal tract. It is suggested that the currently accepted model for these transport processes (the pH partition hypothesis) is an overly simplistic representation of mechanism, and that a more complex, three compartment system is required to fully delineate the characteristics of the transport processes. The proposal includes three types of experiments (1) In vivo studies on the absorption, and secretion of drugs will allow examination of the utility of the three compartment model as a broadly applicable, and fully quantitative description of drug transport mechanisms. (2) In vitro studies on synthetic membranes, and on epithelia will be used to identify, and evaluate the determinants of weak electrolyte permeation. (3) Biophysical, and biochemical approaches will be used to characterize the processes responsible for the establishment of the intra-epithelial pH gradients which are the driving forces for net transport of weak electrolytes across epithelia. The project will focus on the development of physiological, and pharmacological approaches to the regulation of drug transport, and on the roles of the alimentary epithelia as loci of drug interactions. Particular attention will be paid to the significance of the alimentary epithelia in the pharmacokinetics of common drugs of abuse, including the barbiturates, narcotics, and the narcotic antagonists, and to the possibility that modification of the alimentary transport processes may facilitate recovery from intoxication with these substances.